As an organized research unit of the University of Southern California that is administratively located within the Keck School of Medicine, the USC Norris Comprehensive Cancer Center is a matrix organization led by a director. It is composed of more than 200 members from the faculty of several USC professional schools/departments and the College of Letters, Arts and Sciences.

The Director is appointed by and reports to the Dean of the Keck School of Medicine. Members are appointed by the Director of the Cancer Center based on their research interests, funding, and/or clinical practice. The Director is a voting member of the Faculty Executive Committee (department chairs of the medical school), but the Director, unlike the department chairs, does not have direct appointment authority for new faculty.

However, because the Director controls space designated by the University for the Cancer Center as well as considerable gift and grant resources, the Cancer Center has frequently initiated searches for faculty meeting its programmatic needs. In addition, the Cancer Center, like all departments in the Keck School of Medicine, has a budget funded by the school that it uses to support faculty members in various departments, according to the Cancer Center's own needs. In cases where the Cancer Center has initiated the search for a new faculty member, a departmental appointment is negotiated as the search develops and the candidates' qualifications are reviewed.

Any potential appointee must be approved by the appropriate department's faculty and chair prior to a letter of offer. In other cases, where searches are initiated by a department, the department chair may approach the Cancer Center for financial or space resources if the recruitment may meet a Cancer Center need. In either case, the Cancer Center Director signs any letter of offer that commits center resources to the recruitment package.